PROJECT SUMMARY Globally, 1.8 million children are living with HIV-1 and over half of the ~180,000 new infections annually occur postnatally through breast milk transmission. While antiretroviral therapy (ART) has improved disease outcome and reduced transmission, residual immune activation persists during ART and interruption of ART leads to rapid viral rebound due to the latent viral reservoir. Interventions to delay or prevent viral rebound in the absence of ART would be highly beneficial to the pediatric population who must remain on ART throughout their lifespan. In adults, microbial dysbiosis thought to drive disease progression is evident within the first few weeks of HIV-1 infection and is not restored through ART administration. The effect of HIV infection on the developing microbiome and its role in disease progression of infants is not well defined. The objective of this proposal is to provide insight into the microbiome composition and function during SIV infection and investigate the effect of IL-21 as a therapeutic to reduce microbial dysbiosis in SIV-infected ART-suppressed infant rhesus macaques (RMs). IL-21 drives Th17 differentiation, a population of immune cells critical to mucosal immune homeostasis and intestinal epithelial barrier function that are preferentially depleted in early HIV/SIV infection. IL-21 recently showed promising results in adult RMs and is predicted to favorably impact the immune dysfunction induced by HIV-1 infection in infants. The scientific premise is that our novel model of postnatal oral SIV infection and suppressive ART in infant RMs will allow us to generate key data on microbiome composition and function and the impact of a potential therapeutic, IL-21. The central hypothesis is that by restoring Th17 CD4+ T cells through administration of exogenous IL-21, we will reverse microbial dysbiosis that occurs following SIV infection resulting in reduced immune activation and a reduction in both viral reservoirs on ART and set point viremia after ART interruption. We will test this hypothesis in the following Specific Aims: 1) To determine the impact of SIV infection and ART suppression on microbiome development in infant RMs; 2) To determine the impact of IL-21 on the microbiome in SIV-infected ART-suppressed infant RMs. A key feature of this proposal is the use of our novel, highly relevant animal model to perform controlled studies of an innovative immune-based approach that is directly translatable to future clinical trials. We expect that the findings from this proposal will critically inform our understanding of HIV-1 pathogenesis and therapeutic approaches in the pediatric population.